Project Summary Understanding the molecular mechanisms that govern hematopoietic lineage specification and differentiation is critical for developing targeted therapies for bone marrow failure and myeloproliferative disorders. Rcor1 (CoREST) is an established cofactor for the histone demethylase LSD1/KDM1, however its role in regulating hematopoiesis is unknown. Using a conditional knockout model we now demonstrate that myeloerythroid differentiation is profoundly dependent on Rcor1. The overall goal of this proposal is to the identify the mechanisms by which Rcor1 regulates myelomonocytic progenitors. Specifically we will i) Determine the functions of Rcor1 in myelomonocytic progenitors and monocytes; ii) Identify Rcor1 targets in granulocyte precursors and monocytes and iii) Determine the functions of the Rcor1 target genes and pathways in myelomonocytic progenitor cell differentiation. By profiling the transcriptional programs in Rcor1 deficient progenitors, we will identify functionally relevant transcriptional targets of Rcor1. The results of this study will contribute to our understanding of epigenetic regulation of normal hematopoietic progenitor cells and will likely provide important insights relevant to the pathogenesis of bone marrow failure syndromes and myeloproliferative disorders.